Hemofiltration systems, methods and devices used to treat inflammatory mediator related disease

ABSTRACT

A hemofiltration system for a mammal comprises a hemofilter and an adsorbent device. The hemofilter removes ultrafiltrate from a blood stream extracted from the mammal to create a filtered blood stream and an ultrafiltrate stream. The adsorbent device is comprised of one or more adsorbent materials and is used to adsorb inflammatory mediators from the ultrafiltrate stream received from the hemofilter removing inflammatory mediators that cause inflammatory mediator related disease, sepsis, and SIRS/MODS/MOSF to create a post adsorption ultrafiltrate stream. The post adsorption ultrafiltrate stream is selectively combined with the filtered blood stream and together with the filtered blood stream is returned to the mammal.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a Continuation-in-Part Application of U.S.application Ser. No. 09/113,758 filed Jul. 10, 1998 entitledHEMOFILTRATION SYSTEMS, METHODS AND DEVICES USED TO TREAT INFLAMMATORYMEDIATOR RELATED DISEASE, now U.S. Pat. No.______.

TECHNICAL FIELD

[0002] The present invention relates generally to systems, methods, anddevices used for hemofiltration. More specifically, the presentinvention relates to novel systems, methods, and devices forhemofiltration for inflammatory mediator-related diseases (IMRD), whichinclude systemic inflammatory response syndrome (“SIRS”), multiorgansystem dysfunction syndrome (“MODS”), and multiorgan system failure(“MOSF”) (collectively “SIRS/MODS/MOSF”).

BACKGROUND

[0003] Patients with life threatening illness are cared for in hospitalsin the intensive care unit (“ICU”). These patients may be seriouslyinjured from automobile accidents, etc., have had major surgery, havesuffered a heart attack, or may be under treatment for seriousinfection, cancer, or other major disease. While medical care for theseprimary conditions is sophisticated and usually effective, a significantnumber of patients in the ICU will not die of their primary disease.Rather, a significant number of patients in the ICU die from a secondarycomplication known commonly as “sepsis” or “septic shock”. Once again,the proper medical terms for sepsis and septic shock are systemicinflammatory response syndrome (“SIRS”), multiorgan system dysfunctionsyndrome (“MODS”), and multiorgan system failure (“MOSF”) (collectively“SIRS/MODS/MOSF”).

[0004] In short, medical illness, trauma, complication of surgery, and,for that matter, any human disease state, if sufficiently injurious tothe patient, may elicit SIRS/MODS/MOSF. The systemic inflammatoryresponse within certain physiologic limits is beneficial. As part of theimmune system, the systemic inflammatory response promotes the removalof dead tissue, healing of injured tissue, detection and destruction ofcancerous cells as they form, and mobilization of host defenses toresist or to combat infection. If the stimulus to the systemicinflammatory response is too potent, such as massive tissue injury ormajor microbial infection, however, then the systemic inflammatoryresponse may cause symptoms which include fever, increased heart rate,and increased respiratory rate. This symptomatic response constitutessystemic inflammatory response syndrome (“SIRS”). If the inflammatoryresponse is excessive, then injury or destruction to vital organ tissuemay result in vital organ dysfunction, which is manifested in many ways,including a drop in blood pressure, deterioration in lung function,reduced kidney function, and other vital organ malfunction. Thiscondition is known as multiorgan dysfunction syndrome (“MODS”). Withvery severe or life threatening injury or infection, the inflammatoryresponse is extreme and can cause extensive tissue damage with vitalorgan damage and failure. These patients will usually die promptlywithout the use of ventilators to maintain lung ventilation, drugs tomaintain blood pressure and strengthen the heart, and, in certaincircumstances, artificial support for the liver, kidneys, coagulation,brain and other vital systems. This condition is known as multiorgansystem failure syndrome (“MOSF”). These support measures partiallycompensate for damaged and failed organs, they do not cure the injury orinfection or control the extreme inflammatory response which causesvital organ failures.

[0005] In the United States of America each year, SIRS/MODS/MOSFafflicts approximately 400,000-600,000 patients and results in about150,000 deaths. Overall, depending on the number of organ systemsfailing, the mortality rate of MOSF ranges generally from 40 to 100%.For instance, if three (3) or more vital organs fail, death results inmore the 90% of cases. SIRS/MODS/MOSF is the most common cause of deathin intensive care units and is the thirteenth most common cause of deathin the United States of America. SIRS/MODS/MOSF costs about $5 to $10billion yearly for supportive care. In addition, the incidence ofSIRS/MODS/MOSF is on the rise; reported cases increased about 139%between 1979 and 1987. This increase is due to an aging population,increased utilization of invasive medical procedures, immuno suppressivetherapies (e.g. cancer chemotherapy) and transplantation procedures.(Morbidity and Mortality Weekly Report 1990; Detailed Diagnoses andProcedures, National Hospital Discharge Survey, 1993, from CDC/NationalCenter for Health Statistics, 10/95.)

[0006] The detrimental mechanism of SIRS/MODS/MOSF is the excessiveactivation of the inflammatory response. The inflammatory responseconsists of the interaction of various cell systems (e.g.,monocyte/macrophage, neutrophil, and lymphocytes) and various humoralsystems (e.g., cytokine, coagulation, complement, and kallikrein/kinin).Each component of each system may function as an effector (e.g., killingpathogens, destroying tissue, etc.), a signal (e.g., most cytokines), orboth. Humoral elements of the inflammatory response were known as toxicmediators, but are now known collectively as inflammatory mediators(“IM”). IM include various cytokines (e.g., tumor necrosis factor(“TNF”); the interleukins; interferon, etc.), various prostaglandins(e.g., PG I₂, E₂, Leukotrienes), various clotting factors (e.g.,platelet activating factor (“PAF”)), various peptidases, reactive oxygenmetabolites, and various poorly understood peptides which cause organdysfunction (myocardial depressant factor (“MDF”)). These compoundsinteract as a network with the characteristics of network preservationand self amplification. Some of these compounds, such as MDF andpeptidases, are directly injurious to tissue; other compounds, such ascytokines, coordinate destructive inflammation. Infection (e.g.,abscesses and sepsis) is a common complication of critical illness.Certain bacterial exotoxins, endotoxins or enterotoxins are extremelypotent stimuli to SIRS/MODS/MOSF. Infection is the single most commoncause of SIRS leading to MODS/MOSF. The development and use of effectiveantibiotics and other supportive measures have not had a significanteffect on the death rate from MOSF.

[0007] The systemic inflammatory response with its network of systems(e.g., monocyte/macrophage, complement, antibody production,coagulation, kallikrein, neutrophil activation, etc.) is initiated andregulated through the cytokine (“CK”) system and IM's. The CK systemconsists of more than thirty known molecules each of which activates orsuppresses one or more components of the immune system and one or moreCK in the network. The CK network is the dominant control system of theimmune response. The sources of CK's are monocyte/macrophages andendothelial cells and they are produced in every tissue in the body. Keycharacteristics of the CK system are as follows: (i) CK are chemicalsignals coordinating immune system and associated system activities;(ii) commonly, two or more CK will trigger the same action providing a“fail safe” response to a wide variety of different stimuli (thesystemic inflammatory response is critical to the individuals survival;these redundant control signals assure a system response which does notfalter.); (iii) CK and IM concentrations (usually measured in blood)therefore increase in order to stimulate, control, and maintain theinflammatory response proportionally to the severity of the injury orinfection; and (iv) as severity of injury or infection increases, thecytodestructive activity of the system increases resulting in MODS/MOSF.Therefore, high concentrations of CK and IM measured in the patient'sblood, which are sustained over time, correlate with the patients riskof death.

[0008] Major research efforts by the biotechnology industry have soughtcures for SIRS/MODS/MOSF, but none to date have been licensed by theUnited States Food and Drug Administration (“FDA”) for use in humans.There is currently no definitive therapy for SIRS/MODS/MOSF (Dellinger,1997; Natanson, 1994), even though a great deal of research funds havebeen spent on failed therapies for sepsis (Knaus, 1997). Critical caremedicine techniques available to manage SIRS/MODS/MOSF are generallysupportive in that they do not cure SIRS/MODS/MOSF. The biotechnologyindustry, however, has developed a number of prospective treatments forSIRS/MODS/MOSF. The general strategy of these prospective treatments isto identify what is conceived to be a key or pivotal single CK or IM.This single target CK or IM is then inactivated in an attempt to abatethe inflammatory response. The most widely applied technologies used toinactivate CK or IM is binding with monoclonal antibodies (“MoAb”) orspecific antagonists (“SA”). MoAb's and SA's are used because theyeffectively bind the target CK or IM, or its receptor, usually in an“all or none” blockade. This strategy is problematic for two (2)reasons. First, the CK system is essential to mobilize the inflammatoryresponse, and through it, the host immune response. If the CK systemwere blocked, death would ensue from unhealed injury or infection.Second, the CK and IM signals which make up the control network of theimmune response consist of many redundant control loops to assure the“fail safe” initiation and continuation of this critical response. Inthe field of engineering, control theory indicates that a redundant,self amplifying system will not be effectively controlled by blockingone point, such as one CK or IM (Mohler, 1995).

[0009] Also, of interest, note the existing technique of hemofiltration(“HF”), which was developed as a technique to control over hydration andacute renal failure in unstable ICU patients. Existing HF techniques mayuse a hemofilter of some sort, which consists of a cellulose derivativesor synthetic membrane (e.g., polysulfone, polyamide, etc.) fabricated aseither a parallel plate or hollow fiber filtering surface. Since theblood path to, through, and from the membrane is low resistance, thepatients' own blood pressure drives blood through the filter circuit. Inthese HF applications, the hemofilter is part of a blood circuit. Inpassive flow HF, arterial blood flows through a large bore cannula, intoplastic tubing leading to the filter; blood returns from the filterthrough plastic tubing to a vein. This is known as arteriovenous HF.Alternately, a blood pump is used, so that blood is pumped from eitheran artery or a vein to the filter and returned to a vein. This is knownas pumped arterio-venous HF or pumped veno-venous HF. Ultrafiltratecollects in the filter jacket and is drained through the ultrafiltrateline and discarded. Ultrafiltrate flow rates are usually 250 ml-2000ml/hour. In order to prevent lethal volume depletion, a physiologic andisotonic replacement fluid is infused into the patient concurrently withHF at a flow rate equal to or less than the ultrafiltrate flow rate. Thebalance of replacement fluid and ultrafiltrate is determined by thefluid status of the patient.

[0010] The pores of most filter membranes allow passage of molecules upto 30,000 Daltons with very few membranes allowing passage of moleculesup to 50,000 Daltons. The membranes used to treat renal failure weregenerally designed to achieve the following specific goals: (i) topermit high conductance of the aqueous phase of blood plasma waterneeded to permit the formation of ultrafiltrate at a fairly lowtransmembrane pressure (typically 20-40 mm Hg), which requires arelatively large pore size that incidentally passes molecules of up to30,000 to 50,000 Daltons; and (ii) to avoid passage of albumin (e.g.,68,000 Daltons). Note with these existing hemofilters used to treatrenal failure, the ultrafiltrate contains electrolytes and smallmolecules (e.g., urea, creatinine, and uric acid), but no cells and onlypeptides and proteins smaller than the membrane pore size. Thecomposition of the ultrafiltrate is very similar to plasma water. Lossof albumin, and subsequently, oncotic pressure, could cause or aggravatetissue edema and organ dysfunction (e.g., pulmonary edema), sohemofilters are designed to avoid this by having molecular weightexclusion limits well below the molecular weight of albumin (e.g.,68,000 Daltons).

[0011] During filtration of protein containing solutions, colloids orsuspensions, or blood, the accumulation of protein as a gel orpolarization layer occurs on the membrane surface. This gel layertypically reduces effective pore size, reducing the filterable molecularweights by roughly 10-40%. Therefore, pore sizes selected are somewhatlarger than needed, anticipating a reduction in effective size. Thus,present membranes allow filtration and removal of excess water,electrolytes, small molecules and nitrogenous waste while avoiding anyloss of albumin or larger proteins. These membranes are well-suited totheir accepted uses, that is, treatment of over hydration and acuterenal failure in unstable ICU patients.

[0012] Uncontrolled observations in ICU patients indicate that HF, inaddition to controlling over hydration and acute renal failure, isassociated with improvements in lung function and cardiovascularfunction. None of these improvements has been associated with shortenedcourse of ventilator therapy, shortened ICU stay, or improved survival.The usual amount of ultrafiltrate taken in the treatment of overhydration and acute renal failure is 250 to 2000 ml/hour, 24 hours aday. A few published observations have suggested that higher amounts ofultrafiltrate brought about greater improvements in pulmonary andcardiovascular status; these have resulted in the development of atechnique known as high volume HF (“HVHF”). In HVHF, from 2 to 9liters/hour of ultrafiltrate are taken for periods of from 4 to 24 hoursor more. Furthermore, preliminary uncontrolled or poorly controlledstudies suggest that HVHF improves survival in patients withSIRS/MODS/MOSF; there is growing interest in the use of HVHF inSIRS/MODS/MOSF. There is however great hesitance to use HVHF for thefollowing reasons: (i) the high volumes (currently 24-144 liters/day) ofultrafiltrate require equally high volumes of sterile, pharmaceuticalgrade replacement fluid; at these high volumes, errors in measuringultrafiltrate coming out and replacement fluid flowing into the patientcould cause injurious or lethal fluid overload or volume depletion; (ii)the high volume of ultrafiltrate removed could filter out of the blooddesirable compounds from the patient resulting in dangerousdeficiencies; this is currently theoretical, but should be takenseriously; (iii) large volumes of warm (body temperature) ultrafiltrateflowing out of the patient, and large volumes of cool (room temperature)replacement fluid flowing into the patient can cause thermal stress orhypothermia; and (iv) high volumes of replacement fluid add considerableexpense to the therapy.

[0013] HVHF, as currently practiced, uses conventional hemofilters withpore sizes which provide a molecular weight cut of 30,000 Daltons andoccasionally of 50,000 Daltons. The device and process described in U.S.Pat. No. 5,571,418 generally contemplates the use of large porehemofiltration membranes with pore sizes to provide molecular weightexclusion limits of 100,000 to 150,000 Daltons. With these highermolecular weight cutoffs, these membranes are designed to remove a widerrange of different IM's; these large pore membranes should remove excessamounts of all known IM's. These large pore hemofiltration membraneshave been demonstrated in animal studies to be superior to conventionalhemofilter membranes in improving survival time in a swine model oflethal Staphylococcus aureus infection (Lee, PA et al. Critical CareMedicine April 1998). It is anticipated that they will be superior toconventional membranes in SIRS/MODS/MOSF. However, it may be anticipatedthat in HVHF, the large pore membranes may also remove more differentdesirable compounds thus increasing the risk of the negative sideeffects of HVHF.

[0014] Other techniques used in the past to treat acute renal failureand/or SIRS/MODS/MOSF include hemodialysis and plasmapheresis.Hemodialysis is well suited to fluid and small solute (less the 10,000Daltons) removal. However hemodialysis membranes remove very few IM(only those smaller than 5000 to 10,000 Daltons) and so have beenineffective in improving patient condition in SIRS/MODS/MOSF. In theunstable ICU patient, hemodialysis commonly results in rapiddeterioration of cardiovascular function and pulmonary functionrequiring premature termination of the dialysis procedure. Hemodialysishas also been associated with increasing the occurrence of chronic renalfailure in survivors of SIRS/MODS/MOSF. HF was specifically developed(Kramer, 1997) to avoid these complications of hemodialysis and has beenvery successful in doing so.

[0015] Plasmapheresis can be done with both membrane based andcentrifugation based techniques. Plasmapheresis separates plasma and allthat plasma contains from blood, leaving only formed elements. Theremoved plasma is usually replaced by either albumin solution or freshfrozen plasma. The removed plasma would contain all IM's. Studies ofplasmapheresis in animal models of SIRS/MODS/MOSF have shown increasedmortality with plasmapheresis compared to untreated control animals. Nocontrolled study of plasmapheresis in humans with SIRS/MODS/MOSF hasever been done. The expense of albumin and fresh frozen plasma, and therisk of transmission of serious or deadly viral disease with freshfrozen plasma are serious draw backs to the use of plasmapheresis inSIRS/MODS/MOSF.

[0016] Consequently, the prior art remains deficient in the lack ofeffective methods of treating IM related disease (e.g., SIRS/MODS/MOSF),which is safe. Furthermore, while high volume hemofiltration holds somepromises, it is unworkable in its present form and is overly dangerous.The present invention fulfills this longstanding need and desire in thisart.

SUMMARY

[0017] In accordance with teachings of the present disclosure, a systemand method are described for . . .

[0018] Preferred embodiments of the process and system treatinflammatory mediator-related disease, such as sepsis or SIRS/MODS/MOSF.

[0019] Specifically, preferred embodiments of the hemofiltration systemare used in mammals. Preferred embodiments are generally comprised of ahemofilter, blood and ultrafiltrate lines, and an adsorptive device ofone or more chambers containing adsorbent material of one or more types.The hemofilter receives a stream of blood removed from the mammal andremoves ultrafiltrate from the stream of blood from the mammal andthereby creates a stream of filtered blood, which is eventually returnedto the mammal, and a stream of ultrafiltrate. The hemofilter sieves theultrafiltrate, the ultrafiltrate comprised of a fraction of plasmawater, electrolytes, and peptides and small proteins. The sieved bloodpeptides and proteins have a molecular size smaller than the pore sizeof the membrane; IM are included in this group. The hemofilter iscomprised of a biocompatible material. In particular, the hemofilter iscomprised of a membrane and a jacket, wherein the membrane is selectedfrom the group of biocompatible materials (e.g., polysulfone,polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide,polycarbonate, etc.) and cellulose derivatives, and the jacket iscomprised of polycarbonate or some other suitable biocompatiblematerial.

[0020] The adsorptive device is comprised of an encasement jacket. Theadsorptive device incorporates one or more chambers containing adsorbentmaterial of one or more types in the chamber or chambers. The adsorptivedevice receives the stream of ultrafiltrate and selectively ornonselectively removes IM that cause inflammatory mediator-relateddisease, such as sepsis and SIRS/MODS/MOSF, from the ultrafiltrateremoved from the blood of the mammal to create a stream of postadsorption ultrafiltrate. The adsorptive device is preferably comprisedof an encasement jacket comprised of polycarbonate or other suitablebiocompatible material and may be configured as having one or morechambers. Each chamber may contain an adsorbent material or acombination of adsorbent materials. The adsorptive device is designed tobe placed in the line transferring ultrafiltrate removed by thehemofilter and adsorbs IM from the ultrafiltrate producing “postadsorption ultrafiltrate.” The stream of post adsorption ultrafiltrateis eventually combined or reinfused, in whole or in part, with thestream of filtered blood and returned to the mammal. The adsorbentmaterial may be comprised of a host of materials, including, but notlimited to, activated charcoal, uncharged resins, charged resins,silica, immobilized polymyxin B, anion exchange resin, cation exchangeresin, neutral exchange resin, polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, immobilized monoclonal antibodies, immobilized IMreceptors, and immobilized specific antagonists. The adsorbent materialmay also be organized in a number of ways, including a matrix of rods, aporous sieve, a matrix of porous material which conveniently presentsadsorbent materials to ultrafiltrate, and beads. Each adsorbent materialmay be uncoated or coated; the adsorbent material and/or the adsorbentdevice should prevent or contain dissolution and fragmentation ofadsorbent material.

[0021] In addition, preferred embodiments may also be comprised of ablood pump to pump the blood from the mammal, an ultrafiltrate wastepump to pump a portion of the ultrafiltrate to the waste reservoir, anultrafiltrate return pump to pump ultrafiltrate back into the bloodcircuit returning the ultrafiltrate to the patient, a three-way stopcock or a first three-way joint, and a second three-way joint. Firsttubing transfers the blood from the mammal to the blood pump; secondtubing transfers the blood from the blood pump to hemofilter; thirdtubing transfers the filtered blood filtered by the hemofilter to thethree-way joint or three-way stop cock; fourth tubing transfers thefiltered blood along with the post adsorption ultrafiltrate to themammal; fifth tubing transfers the ultrafiltrate to the adsorptivedevice; sixth tubing transfers the post adsorption ultrafiltrate tosecond three-way joint; seventh tubing transfers post adsorptionultrafiltrate to the first ultrafiltrate return pump; eighth tubingtransfers post adsorption ultrafiltrate from the first ultrafiltratereturn pump to three-way joint or three-way stop cock joining fourthtubing which transfers filtered blood along with the post adsorptionultrafiltrate to the mammal; ninth tubing transfers post adsorptionultrafiltrate to second ultrafiltrate waste pump; and tenth tubingtransfers post adsorption ultrafiltrate from second ultra filtrate wastepump to waste reservoir. Note that there are alternate embodiments.

[0022] Finally, alternative preferred embodiments may utilize a singlefilter, which would be a “two-stage” filter, that incorporates both thehemofilter and the adsorptive device containing the adsorbentmaterials(s). Note for the purpose of discarding a portion ofultrafiltrate, a second ultrafiltrate pump can be used along withassociated changes to the necessary tubing.

[0023] Preferred processes to treat IM related diseases andSIRS/MODS/MOSF in a mammal are comprised of the following steps: (a)removing blood from the mammal to create a blood stream; (b) filteringthe blood stream to remove ultrafiltrate from the blood to create anultrafiltrate stream and a filtered blood stream; (c) circulating theultrafiltrate stream to the adsorptive device to remove IM that cause IMrelated disease and SIRS/MODS/MOSF to create a post adsorptionultrafiltrate stream; (d) combining the post adsorption ultrafiltratestream with the filtered blood stream to create a post adsorptionultrafiltrate/filtered blood stream; and (e) returning the postadsorption ultrafiltrate/filtered blood stream to the mammal. Additionalsteps may include after step (a), (a1) pumping the blood stream; andafter step (b), (b1) circulating ultrafiltrate to the ultrafiltratewaste pump and on to the waste reservoir and after step (c), (c1)pumping the post adsorption ultrafiltrate stream circulating the postadsorption ultrafiltrate stream to the post hemofilter blood line, oralternatively, to any convenient tubing or vascular canula which returnspost adsorption ultrafiltrate stream to the mammal's vascular system.

[0024] Preferred embodiments provide a number of advantages, importantfunctions and key features. In particular, the use of preferredembodiments allows the safe use of two stage high volume hemofiltration(“HVHF”) with its improved patient survival, avoids dangerous fluidbalance errors inherent to conventional HVHF, avoids the risk ofdepletion of desirable humoral compounds, avoids or minimizes thermalstress and hypothermia, and avoids the cost of excessive amounts ofreplacement fluid. The immune system has many, redundant CK and IMcontrol loops; several of these loops must be down regulated if systemwide control is to be achieved and death from SIRS/MODS/MOSF prevented.The preferred embodiments address this task.

[0025] Moreover, the use of the adsorptive device comprised of adsorbentmaterial(s) provides additional advantages. Conventional hemofiltration(i.e., hemofiltration performed to treat acute renal failure) usuallyrequires the production of and discard of from about 200 ml to 2,000 mlof ultra filtrate per hour. In patients, if this volume were notreplaced, the loss of fluid would soon lead to dehydration, shock anddeath. In practice, some or all of this hourly loss is replaced eachhour as either medicinal or nutrient solutions, or, in whole or in part,with an isotonic, physiologic, sterile, pharmaceutical grade intravenoussolution known as replacement fluid. The pumps used to controlultrafiltrate and replacement fluid flow are either intravenous fluidpumps or roller pumps adapted for this purpose. These pumps can have anerror of from 5-10% and still be considered acceptable for clinicalpurposes. Bedside nurses monitor actual fluid balance and correcterrors. For conventional hemofiltration, these devices and techniques donot usually introduce serious errors, partly due to the level of fluidextracted, filtered, and replaced. However, various investigators haveadapted hemofiltration for use in SIRS/MODS/MOSF by markedly increasingthe volume of ultrafiltrate taken each hour. As discussed above, thistechnique is known as HVHF and requires that from 2 to 9 liters/hour ofultrafiltrate be taken from the patient. Small, uncontrolled studieswith HVHF suggest that HVHF can significantly improve vital organfunction, shorten the duration of vital organ failure, and improvepatient survival in SIRS/MODS/MOSF.

[0026] Criticisms of HVHF include: (i) the risk of fluid balance errorswith high fluid flux; (ii) the risk of depletion of desirable compounds;(iii) the risk of hypothermia; and (iv) expense. First, with respect tothe risk of high fluid flux, the high volumes of ultrafiltrate (about 48to 150 liters/day) and replacement fluid (about 48 to 150 liters/day),being pumped on current equipment, could result in large and dangerousfluid imbalances. With current equipment, imbalances of as much as 30liters of excess fluid delivered to the patient, or 30 liters of excessfluid removed from the patient could occur. Any error approaching thismagnitude in either direction would be very injurious or lethal to thepatient. Hence, HVHF is considered by many to be dangerous andpotentially deadly. Second, with respect to the risk of depletion ofdesirable compounds, the high volumes of ultrafiltrate (about 48 to 150liters/day) removed from the patient do remove large amounts of IM withresulting improvements in SIRS/MODS/MOSF. However, these high volumesmay also remove desirable compounds with deleterious effects. Thiscriticism is theoretical at this time but should be taken seriously.Third, with respect to the risk of hypothermia, about 48 to 150 litersof warm (body temperature) ultrafiltrate are removed from the patientcausing heat loss, and about 48 to 150 liters of cool (room temperature)replacement fluid is infused into the patient causing cooling. This fluxcauses thermal stress and may cause hypothermia. Thermal stress createsadditional energy demands on these already critically stressed patientsand may compromise there condition. Fourth, with respect to the expense,the high volumes of ultrafiltrate (about 48 to 150 liters/day) requireequal or nearly equal volumes of isotonic, physiologic, sterile, pyrogenfree, pharmaceutical grade replacement fluid (RF). Such fluid isexpensive and in these large quantities would add substantially to thecost of patient care.

[0027] As stated above, the use of the adsorbent device by preferredembodiments addresses these concerns. First, with respect to the risk ofhigh fluid flux, the adsorbent device adsorbs IM from the ultrafiltratethus removing them from the ultrafiltrate; the post adsorptionultrafiltrate may then be reinfused, in whole or in part, back into thepatient. Since post adsorption ultrafiltrate is returned to the patient,in whole or in part, the amount of replacement fluid needed to preservefluid balance in the patient is sharply reduced (to the amount ofultrafiltrate discarded), or eliminated entirely. The volumes ofultrafiltrate discarded and replacement fluid infused will need to beonly those indicated by the patients state of edema (over hydration)and/or needs to accommodate medicinal or nutrient solutions; typically 2to 6 liters per day. These lower volumes of fluid flux (about 2 to 6liters per day) can be safely managed by existing pump technology,pumping errors on these small volumes are well tolerated. Second, withrespect to the risk of depletion of desirable compounds, as all or mostof the ultrafiltrate will be returned to the patient (as post adsorptionultrafiltrate), and as adsorbent material will be selected with asnarrow a range of adsorbed substances as possible and focused on IM, theloss of desirable substances is minimized. Third, with respect to therisk of hypothermia, as warm (body temperature) ultrafiltrate isreturned to the patient, the amount of cool (room temperature)replacement fluid needed will be sharply reduced. This will eliminatethe heat loss which would other wise occur with discard of ultrafiltrateand also eliminate the cooling which would occur by the infusion of coolreplacement fluid. In this way, the stress of hypothermia is eliminated.Fourth, with respect to the expense, the cost of RF varies widelydepending on markets, contract arrangements and other considerations.However, $2 to $10 per liter are typical costs. Thus, HVHF could createan incremental cost of from $96 to $1,500 per day. By reinfusion of postadsorption ultrafiltrate following adsorption of IM's, and soeliminating the need for all or most replacement fluid, this incrementalcost is eliminated. In summary, HVHF is a technique which maysignificantly improve survival in SIRS/MODS/MOSF, however, HVHF createsnew and substantial risks and expenses. Preferred embodiments eliminateor sharply reduce these risks and expenses, and make HVHF much safer andmore cost effective in patients suffering from SIRS/MODS/MOSF.

[0028] Other advantages of the invention and/or inventions describedherein will be explained in greater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] A more complete understanding of the present embodiments andadvantages thereof may be acquired by referring to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numbers indicate like features, and wherein:

[0030] The accompanying drawings are incorporated into and form a partof the specification to illustrate several examples of the presentinventions. These drawings together with the description serve toexplain the principles of the inventions. The drawings are only for thepurpose of illustrating preferred and alternative examples of how theinventions can be made and used and are not to be construed as limitingthe inventions to only the illustrated and described examples. Furtherfeatures and advantages will become apparent from the following and moreparticular description of the various embodiments of the invention, asillustrated in the accompanying drawings, wherein:

[0031]FIG. 1A is a schematic of the physical layout of variouscomponents of a preferred embodiment, including mammal 100, hemofilter102, blood pump 104, first ultra-filtrate pump 106 a and secondultrafiltrate pump 106 b, adsorptive device 108 having one or morechambers containing adsorbent material of one or more types, three-waystop cock or first three-way joint 110, second three-way joint 125, andassociated tubing;

[0032]FIG. 1B is a schematic of the physical layout of variouscomponents of a preferred embodiment, including mammal 100, hemofilter102, blood pump 104, single ultra-filtrate pump 106, adsorptive device108 having one or more chambers containing adsorbent material of one ormore types, three-way stop cock or first three-way joint 110, secondthree-way joint 125, and associated tubing;

[0033]FIG. 2 is a schematic of an alternate physical layout of variouscomponents of a preferred embodiment, including mammal 200, hemofilter202, blood pump 204, first ultra-filtrate pump 206 a and secondultra-filtrate pump 206 b, adsorptive device 208 having one or morechambers containing adsorbent material of one or more types, three-waystop cock or first three-way joint 210, second three-way joint 225, andassociated tubing;

[0034]FIG. 3A is a diagram showing the system flow of a preferredembodiment shown in FIG. 1A;

[0035]FIG. 3B is a diagram showing the system flow of a preferredembodiment shown in FIG. 1B;

[0036]FIG. 4 is a diagram showing the system flow of a preferredembodiment shown in FIG. 2; and

[0037]FIGS. 5A, 5B, and 5C are diagrams showing alternate preferredembodiments of adsorbent device 108 (in FIGS. 1A and 1B) and adsorptivedevice 208 (in FIG. 2).

DETAILED DESCRIPTION

[0038] The preferred embodiment will be described by referring toapparatus showing various examples of how the inventions can be made andused. When possible, like reference characters are used throughout theseveral views of the drawing to indicate like or corresponding parts.

Related Definitions

[0039] As a point of reference, please note the following terms anddefinitions.

[0040] The term “hemofiltration” refers to a process of filtering bloodby a membrane with separation of all formed elements, all proteinslarger than effective pore size of the membrane, and retained plasmawater and solute (these return to the patient) from ultrafiltrate.

[0041] The term “ultrafiltrate” refers to the filtered plasma water andsolute and molecules (including target peptides and proteins containingIM) smaller than effective pore size of the membrane. The term “SystemicInflammatory Response Syndrome” (“SIRS”) refers to the excessive anddysfunctional elaboration by a human patient of inflammatory mediators(“IM”) which results in an excessive and injurious inflammatoryresponse.

[0042] The term “Multiple Organ Dysfunction Syndrome” (“MODS”) refers toSIRS causing injury or destruction to vital organ tissue and resultingin vital organ dysfunction, which is manifested in many ways, includinga drop in blood pressure, deterioration in lung function, reduced kidneyfunction, and other vital organ malfunction.

[0043] The term “Multiple Organ System Failure” (“MOSF”) refers to theclinical syndrome of vital organ dysfunction or failure due to tissueinjury resulting from SIRS. Its mortality rate is approximately 40-100%.

[0044] The term “Inflammatory Mediator Related Disease” (“IMRD”) refersto any disease state characterized by injurious or lethal excessproduction of IM. Diseases commonly included in this category includeLupus Erythematosus, Hemolytic Uremic Syndrome, Bullous Pemphigoid,pemphigus vulgaris, sepsis, SIRS/MODS/MOSF, and the like.

[0045] The term “Inflammatory Mediators” or “IM” refers to aheterogeneous group of chemicals synthesized and released by humantissue. IM include cytokines, prostaglandins, oxygen metabolites,kinins, complement factors, various clotting factors, variouspeptidases, various peptides, various proteins, and various toxicpeptides. The molecular weight range of known IM is 1,000-100,000Daltons.

[0046] The term “Hemofilter” refers to the filter used inhemofiltration. It can be configured in a number of ways, such as aseries of parallel plates or as a bundle of hollow fibers. The bloodpath is from a blood inlet port, through the fibers or between theplates, then to a blood outlet port. Filtration of blood occurs at themembrane with ultrafiltrate forming on the side of the membrane oppositethe blood. This ultrafiltrate accumulates inside the body of the filtercontained and embodied by the filter jacket. This jacket has anultrafiltrate drainage port.

[0047] The term “large pore hemofiltration” refers to the use of amembrane or other types of filtration media which may remove albuminfrom a patient's blood stream. For some applications, a large porehemofilter may have molecular weight exclusion limits equal to orgreater than approximately 69,000 Daltons to treat SIRS, MODS, MOSF andIMRD in accordance with teachings of the present invention. For someapplications large pore hemofiltration, performed in accordance withteachings of the present invention, may permit removal of more albuminfrom a patient's blood stream than some previous hemofiltrationtechniques. However, teachings of the present invention substantiallyreduce or eliminate negative effects from removing increased amounts ofalbumin or other desirable compounds from a patient's blood streamduring large pore hemofiltration. The term “large pore hemofilter”refers to a hemofilter satisfactory for use in providing large porehemofiltration in accordance with teachings of the present invention.

[0048]FIG. 1A is a schematic of the physical layout of variouscomponents of a preferred embodiment, including mammal 100, hemofilter102, blood pump 104, first ultrafiltrate pump 106 a, secondultrafiltrate pump 106 b, adsorptive device 108 having one or morechambers containing adsorbent material of one or more types, three-waystop cock or first three-way joint 110, second three-way joint 125, andassociated tubing. FIG. 1B is similar to FIG. 1A, except that singleultrafiltrate pump 106 is used in lieu of first ultrafiltrate pump 106 aand second ultrafiltrate pump 106 b. Both FIGS. 1A and 1B positionthree-way stop cock or first three-way joint 110 in such a manner thatit divides ultrafiltrate stream downstream from adsorptive device 108.FIG. 2 is an alternate schematic of the physical layout of variouscomponents of a preferred embodiment shown in FIGS. 1A and 1B, exceptthat three-way stop cock or first three-way joint 210 dividesultrafiltrate stream before adsorptive device 208. FIGS. 3A and 3B arediagrams showing the system flow of a preferred embodiment shown inFIGS. 1A and 1B, respectively. FIG. 4 is a diagram showing the systemflow of a preferred embodiment shown in FIG. 2.

[0049] Steps 301 and 302 (in FIGS. 3A and 3B) and steps 401 and 402 (inFIG. 4) show blood being continuously withdrawn from mammal 100 (inFIGS. 1A and 1B) and mammal 200 (in FIG. 2) and directed to blood pump104 (in FIGS. 1A and 1B) and blood pump 204 (in FIG. 2) via first tubing101 (in FIGS. 1A and 1B) and first tubing 201 (in FIG. 2). Specifically,step 303 (in FIG. 3A and 3B) and step 403 (in FIG. 4) show thecontinuous pumping of blood by blood pump 104 into hemofilter 102 viasecond tubing 103 (in FIGS. 1A and 1B) and by blood pump 204 intohemofilter 202 via second tubing 203 (in FIG. 2). Mammal 100 (in FIGS.1A and 1B) and mammal 200 (in FIG. 2), such as a human being, preferablyhave a major blood vessel cannulated allowing for the continuouswithdrawal of blood by blood pump 104 (in FIGS. 1A and 1B) and bloodpump 204 (in FIG. 2). As shown in steps 304 and 306 (in FIGS. 3A and 3B)and steps 404 and 406 (in FIG. 4), hemofilter 102 ultra-filtrates bloodextracted from mammal 100 (in FIGS. 1A and 1B) and hemofilter 202ultra-filtrates blood extracted from mammal 200 (in FIG. 2). And, step305 (in FIGS. 3A and 3B) and step 405 (in FIG. 4) returns blood filteredby hemofilter 102 to mammal 100 via third tubing 105 and fourth tubing107 in FIGS. 1A and 1B and by hemofilter 202 to mammal 200 via thirdtubing 205 and fourth tubing 207 in FIG. 2.

[0050] Referring to FIGS. 1A, 1B, and 2, ultrafiltration is a filtrationprocess in which blood cells and blood proteins with a molecular sizelarger than the pore size of hemofilter membrane 109 (in FIGS. 1A and1B) and hemofilter membrane 209 (in FIG. 2) are retained in the bloodpath. The composition of hemofilter membrane 109 (in FIGS. 1A and 1B)and hemofilter membrane 209 (in FIG. 2) are preferably comprised ofbiocompatible material, such as polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, etc., but is not limited to these materials. Thejacket of the hemofilter will be preferably comprised of a biocompatiblematerial, such as polycarbonate, but not limited to, polycarbonate.Hemofilter membrane 109 (in FIGS. 1A and 1B) and hemofilter membrane 209(in FIG. 2) are preferably organized as a parallel plate membrane or asa membrane hollow fiber. Preferred embodiments use a hemofilterincorporating the techniques and materials discussed in U.S. Pat. No.5,571,418, which is herein incorporated by reference, which discussesthe use of large pore hemofiltration membranes for hemofiltrationprocesses. Hemofilter membrane 109 in FIGS. 1A and 1B and hemofiltermembrane 209 in FIG. 2 are preferably comprised of large porehemofiltration membranes, which are preferably fabricated from anybiocompatible material suitable for the purpose such as polysulfone,polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide,polycarbonate, cellulose derivatives, etc., but, of course, withoutlimitation to these materials.

[0051] As shown in step 304 in FIGS. 3A and 3B, hemofilter membrane 109(in FIGS. 1A and 1B) sieves a fraction of plasma water, electrolytes,blood peptides and proteins with a molecular size smaller than the poresize of the membrane to form ultrafiltrate stream 111 (in FIGS. 1A and1B), which is directed to adsorptive device 108 (in FIGS. 1A and 1B),which has one or more chambers containing adsorbent material of one ormore types, via fifth tubing 112 (in FIGS. 1A and 1B). As shown in step307 in FIGS. 3A and 3B, adsorptive device 108 is perfused byultrafiltrate stream 111. Similarly, as shown in step 404 in FIG. 4,hemofilter membrane 209 (in FIG. 2) sieves a fraction of plasma water,electrolytes, blood peptides and proteins with a molecular size smallerthan the pore size of the membrane to form ultrafiltrate stream 211 (inFIG. 2), which is directed to adsorptive device 208 (in FIG. 2), whichhas one or more chambers containing adsorbent material of one or moretypes, via fifth tubing 212, and sixth tubing 215 (in FIG. 2). As shownin step 407 in FIG. 4, adsorptive device 208 is perfused byultrafiltrate stream 211.

[0052] As shown in steps 308 in FIGS. 3A and 3B, ultrafiltrate stream115 (in FIGS. 1A and 1B) is divided at three-way stop cock or firstthree-way joint 110 (in FIGS. 1A and 1B), after adsorptive device 108 inFIGS. 1A and 1B. As shown by step 408 in FIG. 4, ultrafiltrate stream211 (in FIG. 2) is divided at three-way stop cock or first three-wayjoint 210 (in FIG. 2), before adsorptive device 208 in FIG. 2.

[0053] Specifically, in FIG. 1A, after three-way stop cock or firstthree-way joint 110 divides post-adsorptive ultrafiltrate stream 115,discard ultrafiltrate stream 127 is directed toward secondultra-filtrate pump 106 b and to waste reservoir 119 and returnultrafiltrate stream 131 is directed toward first ultra-filtrate pump106 a and on to mammal 100. In FIG. 1B, ultrafiltrate stream 115 isdirected toward single ultrafiltrate pump 106 and discard ultrafiltratestream 121 is directed to waste reservoir 119 and return ultrafiltratestream 129 is returned to mammal 100. In FIG. 2, ultrafiltrate stream211 is directed toward three stop cock 210 and discard ultrafiltratestream 221 is directed toward second ultrafiltrate pump 206 b and thenonto waste reservoir 219 and return ultrafiltrate stream 229 is directedtoward first ultrafiltrate pump 206 a and eventually returned to mammal200.

[0054] Adsorptive device 108 (in FIGS. 1A and 1B) and adsorptive device208 (in FIG. 2) have one or more chambers containing adsorbentmaterials(s). The adsorbent material(s) is (are) preferably fixed orcontained within the respective adsorbent device and none will pass intothe ultrafiltrate stream or return to mammal 100 (in FIGS. 1A and 1B)and mammal 200 (in FIG. 2). The adsorbent materials used in thepreferred embodiment may be coated or uncoated. The nature of theadsorbent materials used in the preferred embodiment is such thatsolutes to be adsorbed will be bound to the adsorbent materials. Asshown in FIGURE 5A, 5B, and 5C, adsorbent material is presented toultrafiltrate flow by structures such as rods or plates, or flowsthrough structures such as beads or porous matrix of any configurationeffective in presentation of adsorptive material(s) to ultrafiltratestream, or flows through one or more chambers containing immobilizedparticulate, beaded or fragmented adsorbent material. Adsorbentmaterials may include, but are not limited to: silica, activatedcharcoal, nonionic resins, ionic resins, immobilized polymyxin B, anionexchange resin, cation exchange resin, neutral exchange resin,immobilized monoclonal antibodies, immobilized IM receptors, immobilizedspecific antagonists, cellulose and its derivatives, synthetic materials(e.g., polysulfone, polyacrylonitrile, polymethylmethacrylate,polyvinyl-alcohol, polyamide, polycarbonate, etc.) and the like or anycombination thereof. The selection of adsorbent materials depends on theinflammatory mediators to be removed. Preferred embodiment usespolymyxin to remove endotoxin, anti-TNF antibody to remove TNF,polyacrylonitrile to remove interleukin 1-beta and TNF, among otheradsorbents, both specific and nonspecific. Adsorbents may also be usedin various combinations as the patients condition and stage of diseasewarrant.

[0055]FIGS. 5A, 5B, and 5C are diagrams showing preferred embodiments ofadsorptive device 108 (in FIG. 1A and 1B) and adsorptive device 208 (inFIG. 2), both of which have one or more chambers containing adsorbentmaterial of one or more types. Adsorbent materials vary widely in theiradsorptive capacity, and types and conditions of substances adsorbed. IMare of many different chemical types (e.g. peptides, lipids) and eachIM's charge and plasma binding (e.g., specific or nonspecificcirculating soluble receptors) will vary the characteristics of how theymay be adsorbed during the course of any inflammatory mediator relateddisease (“IMRD”) or episode of SIRS/MODS/MOSF. For this reason, variousadsorbent materials will be used in order to provide the range ofchemical binding characteristics and capacity needed for removal of manyIM from ultrafiltrate. As stated above, adsorbent materials are ofdifferent chemical and physical types. Particulate adsorbent materials(e.g. charcoal; beads of polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, and similar materials; liposomes, etc.) may becoated or uncoated, but are usually encased in a porous flexible meshsac or rigid porous containment jacket which allows free access ofperfusing fluid (e.g. ultrafiltrate) but contains the particles andprevents them from being carried back to the mammal in the ultrafiltratestream. Some adsorbents (e.g. silica gel) lend themselves to being castor otherwise fabricated in various rigid or semirigid configurations(e.g. rods, plates etc.) which allow for effective and convenientpresentation of ultrafiltrate containing IM to the adsorbent material.Some adsorbents (e.g. monoclonal antibodies, IM receptors, specificantagonists, polymyxin B) will need to be affixed to a supporting matrixof biocompatible material (e.g. polycarbonate and the like) forpresentation of adsorbent material to the ultrafiltrate streamcontaining IM. The matrix of biocompatible material will be configuredto allow effective and convenient presentation of ultrafiltratecontaining IM to the affixed adsorbent material.

[0056] Depending on physical and chemical compatibilities of theadsorbent materials, and the requirements of adequate ultrafiltrateflow, adsorbent device 108 (in FIGS. 1A and 1B) and adsorbent device 208(in FIG. 2) may be configured as one chamber containing one or moreadsorbent materials, as shown in adsorptive device 508 in FIG. 5A andadsorptive device 510 in FIG. 5B, or separated into multiple chamberseach containing one or more adsorbent materials, as shown in adsorptivedevice 512 in FIG. 5C. Adsorbent devices 508 (in FIG. 5A), 510 (in FIG.5B), and 512 (in FIG. 5C) have an inlet port to which the ultrafiltratetubing which carries the ultrafiltrate from hemofilter 108 (in FIGS. 1Aand 1B) and hemofilter 208 (in FIG. 2) will be attached to provideultrafiltrate flow to adsorbent devices 508, 510, or 512. Ultrafiltrateflow through adsorbent device 508 (in FIG. 5A), 510 (in FIG. 5B), and512 (in FIG. 5C), perfuses the adsorbent materials allowing foradsorption of IM, and flows out of the adsorbent device through anoutlet port.

[0057] Referring to FIG. 5C, where a multiple chamber configuration isused for adsorptive device 512, the chambers will be separated by ascreen or other porous barrier which retains the adsorbent materials orcombinations of adsorbent materials in their separate compartments andallows free flow of ultrafiltrate through adsorptive device 512. Analternative embodiment utilizes separate, exchangeable modules eachcontaining an adsorbent material or adsorbent materials. A module or acombination of modules may be inserted into the adsorbent device toprovide for the adsorption of different types of IM as the condition ofthe mammal may require. Although not shown, adsorbent device 108 (inFIGS. 1A and 1B) and adsorptive device 208 (in FIG. 2) can beincorporated into or combine with hemofilter 102 (in FIGS. 1A and 1B)and hemofilter 202 (in FIG. 2), respectively. In this embodimentultrafiltrate formed at the hemofilter membrane will pass into thehemofilter jacket, the hemofilter jacket will incorporate the adsorptivematerials in one or more chambers and ultrafiltrate will flow throughthe adsorbent materials. Ultrafiltrate will transfer from the combinedhemofilter/adsorbent device through an outlet port to post adsorbentultrafiltrate tubing.

[0058] The amount of blood continuously pumped will be operatordetermined and depend on the condition of mammal 100 (in FIGS. 1A and1B) and mammal 200 (in FIG. 2) and the needs of effective HF. The amountof blood continuously removed must be determined on a case by casebasis. The flow rate, the amount of blood removed and the duration ofthe HF therapy are determined by the weight, the age and the nature andseverity of illness of mammal. Typically, blood flow rates range from100 to 200 ml/minute. The rate of ultrafiltration depends on the natureand severity of illness and is indexed to body weight, total body waterand/or clinical indices of disease management (e.g., pulmonary function,cardiovascular status, etc.). Typically, total ultrafiltrate flow rateis 1 to 9 liters/hour of which from 0 to 2 liters/hour may be discarded.The discard rate will be determined by the fluid balance requirements ofthe mammal. The amount of ultrafiltrate discarded will be determined byoperator as operator judges the needs of mammal 100 and mammal 200 forfluid removal. All ultrafiltrate not discarded is returned to mammal 100(in FIGS. 1A and 1B) and mammal 200 (in FIG. 2).

[0059] With respect to the tubing used in preferred embodiments fortubing, the composition of the material making up the blood pump tubing,ultrafiltrate tubing, etc, is preferably of a biocompatible material,such as polyvinylchloride, but not limited to this material. The tubingwill be flexible and have outside diameters complementary to theappropriate hemofilter connections, adsorptive device connections,joints, stop cocks, or pump heads.

[0060] Specifically, with respect to the tubing in FIG. 1A, first tubing101 transfers blood from mammal 100 to blood pump 104; second tubing 103transfers blood from blood pump 104 to hemofilter 102; third tubing 105transfers the filtered blood filtered by hemofilter 102 to secondthree-way joint 125; fourth tubing 107 transfers the filtered bloodalong with the post adsorption ultrafiltrate to mammal 100; fifth tubing112 transfers the ultrafiltrate to adsorptive device 108; sixth tubing123 transfers the post adsorption ultrafiltrate to three-way stop cockor second three-way joint 110; seventh tubing 131 transfers postadsorption ultrafiltrate to first ultrafiltrate pump 106 a; eighthtubing 129 transfers post adsorption ultrafiltrate from firstultrafiltrate pump 106 a to second three-way joint 125 joining fourthtubing 107 which transfers filtered blood along with the post adsorptionultrafiltrate to the mammal; ninth tubing 127 transfers post adsorptionultrafiltrate to second ultrafiltrate pump 106 b; and tenth tubing 121transfers post adsorption ultrafiltrate from second ultra filtrate pump106 b to waste reservoir 119. First ultrafiltrate pump 106 a andassociated tubing implement steps 311 and 312 in FIG. 3A; secondultrafiltrate pump 106 b, waste reservoir 119, and associated tubingimplement steps 309 and 310 in FIG. 3A.

[0061] With respect to the tubing in FIG. 1B, first tubing 101 transfersblood from mammal 100 to blood pump 104; second tubing 103 transfersblood from blood pump 104 to hemofilter 102; third tubing 105 transfersthe filtered blood filtered by hemofilter 102 to second three-way joint125; fourth tubing 107 transfers the filtered blood along with the postadsorption ultrafiltrate to mammal 100; fifth tubing 112 transfers theultrafiltrate to adsorptive device 108; sixth tubing 123 transfers thepost adsorption ultrafiltrate or ultrafiltrate stream 115 to singleultrafiltrate pump 106; seventh tubing 127 transfers post adsorptionultrafiltrate from ultrafiltrate pump 106 to three-way stop cock orfirst three-way joint 110; eighth tubing 129 transfers post adsorptionultrafiltrate from three-way stop cock or first three-way joint 110 tosecond threeway way joint 125 joining fourth tubing 107 which transfersfiltered blood along with the post adsorption ultrafiltrate to mammal100; and ninth tubing 121 transfers post adsorption ultrafiltrate fromthree-way stop cock or first three-way joint 110 to waste reservoir 119.Single ultrafiltrate pump 106 and associated tubing implement step 351in FIG. 3B; waste reservoir 119 and associated tubing implement step 310in FIG. 3B. Second three-way joint 125 and associated tubing implementstep 312 in FIG. 3B.

[0062] With respect to the tubing in FIG. 2, first tubing 201 transfersblood from mammal 200 to blood pump 204; second tubing 203 transfersblood from blood pump 204 to hemofilter 202; third tubing 205 transfersthe filtered blood filtered by hemofilter 202 to second three-way joint225; fourth tubing 207 transfers the filtered blood along with the postadsorption ultrafiltrate to mammal 200; fifth tubing 212 transfers theultrafiltrate to three-way stop cock or first three-way joint 210; sixthtubing 215 transfers the ultrafiltrate from three-way stop cock or firstthree-way joint 210 to adsorptive device 208; seventh tubing 229transfers the post adsorption ultrafiltrate or ultrafiltrate stream 215to first ultrafiltrate pump 206 a; eighth tubing 223 transfers postadsorption ultrafiltrate from first ultrafiltrate pump 206 a to secondthree-way joint 225 joining fourth tubing 207 which transfers filteredblood along with the post adsorption ultrafiltrate to mammal 200; ninthtubing 225 transfers ultrafiltrate from three-way stop cock or firstthree-way joint 210 to second ultrafiltrate pump 206 b; and tenth tubing233 transfers ultrafiltrate from second ultrafiltrate pump 206 b towaste reservoir 219. First ultrafiltrate pump 206 a and associatedtubing implement steps 411 and 412 in FIG. 4; second ultrafiltrate pump206 b and waste reservoir 219 and associated tubing implement steps 409and 410 in FIG. 4.

Further Modifications and Variations

[0063] Although the invention has been described with reference to aspecific embodiment, this description is not meant to be construed in alimiting sense. The example embodiments shown and described above areonly intended as an example. Other applications of the preferredembodiments may be found as well. Various modifications of the disclosedembodiment as well as alternate embodiments of the invention will becomeapparent to persons skilled in the art upon reference to the descriptionof the invention. For instance, structural modification could includethe integration of hemofilter 102 in FIGS. 1A and 1B and hemofilter 202in FIG. 2 with adsorptive device 108 (in FIGS. 1A and 1B) and adsorptivedevice 208 (in FIG. 2), both of which have one or more chamberscontaining adsorbent material of one or more types, with elimination ofthe additional tubing. In this embodiment ultrafiltrate formed in jacketof hemofilter 102 (in FIGS. 1A and 1B) and hemofilter 202 (in FIG. 2)would be presented directly to adsorbent material contained with inhemofilter jacket or in a chamber or chambers directly contiguous withhemofilter jacket. The chamber containing ultrafiltrate would be drainedby ultrafiltrate line. Ultrafiltrate would be continuously pumped andapportioned for discard or returned to mammal 100 (in FIGS. 1A and 1B)and mammal 200 (in FIG. 2). In addition, it is possible to modify theconfiguration of ultrafiltrate lines to provide for infusion ofultrafiltrate into mammal 100 (in FIGS. 1A and 1B) or mammal 200 (inFIG. 2) via a vascular cannula in a blood vessel and separate from thehemofiltration circuit. Furthermore, note the ultrafiltrate return pumpand the ultrafiltrate discard pump in the preferred embodiment shown anddiscussed above may be combined into a single two head ultrafiltratepump system. Also, note while the ultrafiltrate return pump and theultrafiltrate discard pump are shown in the figures as two separatepumps, it is within the scope of the invention to combine two pumps intoa single pump, and thus, the separate pumps may be interpreted as twoparts of a single pump.

[0064] Modifications of adsorbent device will be determined by theinflammatory mediator related disease (IMRD) to be treated and the phaseof the disease. Various regions of the IM network are dominant atdifferent phases of an IMRD and different IMRD exhibit differentpatterns of IM networking. Thus a different adsorbent material ormaterials, or different groupings of adsorbent materials will be neededfor different IMRD's in their different phases. Thus different adsorbentdevices will be developed as more is learned of IMRD's and their phases.Adsorbent devices may contain a fixed adsorbent material or a fixedcombination of adsorbent materials. Alternatively, an adsorbent devicemay be configured with different, interchangeable modules of adsorbentmaterials to be adapted to the changing dominance of the IM network. Themodules may consist of one or more chambers containing adsorbentmaterial of one or more types. The adsorbent device may be designed toaccept modules of adsorbent materials inserted in place as dictated bypatient need and operator assessment.

[0065] Different configurations of adsorbent materials will be used.Adsorbent materials exhibit chemical characteristics which determinewhat physical form will provide the greatest stability in flowingultrafiltrate. Adsorbent material must remain irreversibly bound to itssupporting matrix, or in the case of beads (e.g. polysulfone,polyacrylonitrile, etc) or particulates (e.g. charcoal) inescapablycontained in mesh or other containment device. Adsorbent material,matrix, and containment material can not be allowed to dissolve,dissociate or fragment into the ultrafiltrate to be infused into themammal. Adsorbent material, matrix, and containment material must beconfigured to provide physical durability, and adequate porosity andconfiguration for optimal presentation of adsorbent material to flowingultrafiltrate. Some configurations of matrix are shown in FIGS. 5A, 5B,and 5C. Adsorbent devices of one or more chambers containing adsorbentmaterial of one or more types could be used in series, in whichultrafiltrate flows from the first to subsequent adsorbent devices. Thesequence, number and type of adsorbent devices would be determined byoperator to meet the needs of mammal. Alternatively, the ultrafiltratestream could be divided by a manifold with distribution of ultrafiltrateto adsorbent devices arranged in a parallel configuration, with eachline from each adsorbent device either returned to a manifold andreunited into a single ultrafiltrate line, or each line individuallyapportioned for return to mammal and discard.

[0066] Thus, even though numerous characteristics and advantages of thepresent inventions have been set forth in the foregoing description,together with details of the structure and function of the inventions,the disclosure is illustrative only, and changes may be made in thedetail, especially in matters of shape, size and arrangement of theparts within the principles of the inventions to the full extentindicated by the broad general meaning of the terms used in the attachedclaims. Accordingly, it should be understood that the modifications andvariations suggested above and below are not intended to be exhaustive.These examples help show the scope of the inventive concepts, which arecovered in the appended claims. The appended claims are intended tocover these modifications and alternate embodiments.

[0067] In short, the description and drawings of the specific examplesabove are not intended to point out what an infringement of this patentwould be, but are to provide at least one explanation of how to make anduse the inventions contained herein. The limits of the inventions andthe bounds of the patent protection are measured by and defined in thefollowing claims.

What is claimed is:
 1. A method for treating inflammatory mediatorrelated diseases such as sepsis, septic shock, systemic inflammatoryresponse syndrome, multiple organ system dysfunction syndrome, andmultiple organ system failure in a mammal comprising; pumping blood fromthe mammal using a blood pump; transferring the blood from the bloodpump to a hemofilter; removing an ultrafiltrate from the blood using thehemofilter to create a filtered blood stream and an ultrafiltratestream; transferring the ultrafiltrate stream from the hemofilter to anadsorptive device containing at least one fixed adsorbent material;selectively removing at least one inflammatory mediator which causes aninflammatory mediator related disease from the ultrafiltrate streamusing the adsorbent material to create a post adsorption ultrafiltratestream; combining at least a portion of the post adsorptionultrafiltrate stream with the filtered blood stream and returning thecombined post adsorption ultrafiltrate stream and the filtered bloodstream to the mammal; and transferring any portion of the postadsorption ultrafiltrate stream which is not returned to the mammal to awaste reservoir.
 2. The method of claim 1 further comprisingtransferring the post adsorption ultrafiltrate stream from theadsorptive device using an ultrafiltrate pump.
 3. The method of claim 1further comprising: transferring the post adsorption ultrafiltratestream from the adsorptive device using a first ultrafiltrate pump; andtransferring any portion of the post adsorption ultrafiltrate streamwhich is not returned to the mammal to the waste reservoir using asecond ultrafiltrate pump.
 4. A hemofiltration system to treat aninflammatory mediator related disease in a mammal, comprising: a largepore hemofilter operable to remove ultrafiltrate from a blood streamextracted from the mammal and to create a filtered blood stream and anultrafiltrate stream; the hemofilter having a membrane with at least onepore having a pore size larger than approximately 69,000 Daltons; anadsorptive device containing at least one adsorbent material operable toreceive the ultrafiltrate stream from the hemofilter and to remove awide range of inflammatory mediators therefrom to create a postadsorption ultrafiltrate stream; the adsorbent material selected from agroup consisting of coated materials, uncoated materials, a matrix ofrods, a matrix configured for convenient presentation of ultrafiltrateto adsorbent material, beads, and particulates and any combinationthereof; and tubing for use in combining the post adsorptionultrafiltrate stream with the filtered blood stream and returning thecombined stream to the mammal.
 5. The hemofiltration system of claim 4 ,wherein the adsorbent material is comprised of adsorbent resins selectedfrom a group consisting of immobilized polymyxin B,polystyrene-derivative fibers, cation exchange resins, neutral exchangeresins, anion exchange resins, cellulose materials, polysulfone,polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide,polycarbonate, cellulose derivatives, specific antibody coatedmaterials, specific antagonist coated materials, and any combinationthereof.
 6. The hemofiltration system of claim 4 , wherein theultrafiltrate stream comprises plasma water, electrolytes, bloodpeptides and proteins.
 7. The hemofiltration system of claim 4 , whereinthe hemofilter comprises a membrane and a jacket, wherein the membraneis selected from the group of polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, andcellulose derivatives, and the jacket comprises polycarbonate.
 8. Theprocess of claim 4 , wherein the adsorbent material is selected from agroup consisting of activated charcoal, uncharged resins, chargedresins, silica, immobilized polymyxin B, anion exchange resin, cationexchange resin, neutral exchange resin, polysulfone, polyacrylonitrile,polymethyl-methacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, immobilized monoclonal antibodies, immobilized IMreceptors, immobilized specific antagonists, and any combinationthereof.
 9. A method for treating inflammatory mediator related diseasesuch as sepsis, septic shock, and inflammatory mediator-related diseasessuch as systemic inflammatory response syndrome, multiple organ systemdysfunction syndrome, and multiple organ system failure in a mammalcomprising; pumping blood from the mammal using a blood pump;transferring the blood from the blood pump to a hemofilter; removing anultrafiltrate from the blood using the hemofilter to create a filteredblood stream and an ultrafiltrate stream; transferring the ultrafiltratestream from the hemofilter to an adsorptive device containing at leastone fixed adsorbent material; selectively removing at least oneinflammatory mediator which causes an inflammatory mediator relateddisease from the ultrafiltrate stream using the adsorbent material tocreate a post adsorption ultrafiltrate stream; combining at least aportion of the post adsorption ultrafiltrate stream with the filteredblood stream and returning the combined post adsorption ultrafiltratestream and the filtered blood stream to the mammal; and transferring anyportion of the post adsorption ultrafiltrate stream which is notreturned to the mammal to a waste reservoir.
 10. The method of claim 9further comprising transferring the post adsorption ultrafiltrate streamfrom the adsorptive device using an ultrafiltrate pump.
 11. The methodof claim 9 further comprising: transferring the post adsorptionultrafiltrate stream from the adsorptive device using a firstultrafiltrate pump; and transferring any portion of the post adsorptionultrafiltrate stream which is not returned to the mammal to the wastereservoir using a second ultrafiltrate pump.
 12. A hemofiltration systemto treat an inflammatory mediator related disease such as sepsis andseptic shock in a mammal, comprising: a hemofilter operable to removeultrafiltrate from a blood stream extracted from the mammal and tocreate a filtered blood stream and an ultrafiltrate stream; thehemofilter having a membrane having at least one pore with a pore sizeselected to be larger than a molecular size of the blood peptides andproteins; an adsorptive device containing at least one adsorbentmaterial operable to receive the ultrafiltrate stream from thehemofilter and to remove at lease one inflammatory mediator therefrom tocreate a post adsorption ultrafiltrate stream; the adsorbent materialselected from a group consisting of coated materials, uncoatedmaterials, a matrix of rods, a matrix configured for convenientpresentation of ultrafiltrate to adsorbent material, beads, andparticulates and any combination thereof; and means for selectivelycombining the post adsorption ultrafiltrate stream with the filteredblood stream and returning the combined stream to the mammal.
 13. Thehemofiltration system of claim 12 , wherein the adsorbent material iscomprised of adsorbent resins selected from a group consisting ofimmobilized polymyxin B, polystyrene-derivative fibers, cation exchangeresins, neutral exchange resins, anion exchange resins, cellulosematerials, polysulfone, polyacrylonitrile, polymethylmethacrylate,polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives,specific antibody coated materials, specific antagonist coatedmaterials, and any combination thereof.
 14. The hemofiltration system ofclaim 12 , wherein the ultrafiltrate stream comprises plasma water,electrolytes, blood peptides and proteins.
 15. The hemofiltration systemof claim 12 , wherein the hemofilter comprises a membrane and a jacket,wherein the membrane is selected from the group of polysulfone,polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide,polycarbonate, and cellulose derivatives, and the jacket comprisespolycarbonate.
 16. The process of claim 12 , wherein the adsorbentmaterial is selected from a group consisting of activated charcoal,uncharged resins, charged resins, silica, immobilized polymyxin B, anionexchange resin, cation exchange resin, neutral exchange resin,polysulfone, polyacrylonitrile, polymethyl-methacrylate,polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives,immobilized monoclonal antibodies, immobilized IM receptors, immobilizedspecific antagonists, and any combination thereof.
 17. A hemofiltrationsystem to treat an inflammatory mediator related disease such as sepsisand septic shock in a mammal comprising: a blood pump to pump blood fromthe mammal; a first tubing to transfer the blood from the mammal to theblood pump; a hemofilter to receive the blood removed from the mammal,the hemofilter operable to remove an ultrafiltrate from the blood tocreate a filtered blood stream and an ultrafiltrate stream; a secondtubing to transfer the blood from the blood pump to the hemofilter; athird tubing to transfer the filtered blood stream from the hemofilterto the mammal; an adsorptive device containing at least one fixedadsorbent material to receive the ultrafiltrate stream from thehemofilter; the adsorbent material operable to remove inflammatorymediators that cause the inflammatory mediator related disease from theultrafiltrate stream to create a post adsorption ultrafiltrate stream; afourth tubing to transfer the ultrafiltrate stream from the hemofilterto the adsorptive device; means for selectively combining the postadsorption ultrafiltrate stream with the filtered blood stream andreturning the combined stream of post adsorption ultrafiltrate and thefiltered blood to the mammal including a fifth tubing to transfer thepost adsorption ultrafiltrate stream from the adsorptive device; a sixthtubing to transfer the combined stream of post adsorption ultrafiltrateand the filtered blood to the mammal; and an seventh tubing to transferany of the post adsorption ultrafiltrate which is not combined with thefiltered blood to a waste reservoir.
 18. The hemofiltration system ofclaim 17 , wherein the adsorbent material is selected from a groupconsisting of activated charcoal, uncharged resins, charged resins,silica, immobilized polymyxin B, anion exchange resin, cation exchangeresin, neutral exchange resin, polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, immobilized monoclonal antibodies, immobilized IMreceptors, immobilized specific antagonists, and any combinationthereof.
 19. The hemofiltration system of claim 17 , wherein theadsorptive device prevents dissolution and fragmentation of theadsorbent material.
 20. The hemofiltration system of claim 17 , whereinthe adsorbent material is comprised of adsorbent resins selected from agroup consisting of immobilized polymyxin B polystyrene-derivativefibers, anion exchange resins, cation exchange resins, neutral exchangeresins, cellulose materials, polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate,cellulose derivatives, specific antagonist coated materials and specificantibody coated materials.
 21. The hemofiltration system of claim 17 ,wherein the ultrafiltrate comprising plasma water, electrolytes, bloodpeptides, proteins, carbohydrates, and lipids.
 22. The hemofiltrationsystem of claim 17 wherein the hemofilter comprises a membrane having atleast one pore with a pore size wherein the pore size of the membrane isselected such that blood peptides and proteins are filteredtherethrough.
 23. A hemofiltration system to treat an inflammatorymediator related disease such as sepsis and septic shock in a mammal,comprising: a hemofilter to receive blood removed from the mammal, thehemofilter operable to remove an ultrafiltrate from the blood removedfrom the mammal to create filtered blood; an adsorptive devicecontaining at least one fixed adsorbent material to receive theultrafiltrate removed from the blood removed from the mammal, theadsorbent material operable to remove inflammatory mediators that causethe inflammatory mediator related disease from the ultrafiltrate tocreate post adsorption ultrafiltrate; the adsorbent material selectedfrom a group consisting of coated materials, uncoated materials, amatrix of rods, a matrix configured for convenient and effectivepresentation of ultrafiltrate to adsorbent materials, beads, andparticulates and any combination thereof; means for combining at least aportion of the post adsorption ultrafiltrate with at least a portion ofthe filtered blood and returning the combined post adsorptionultrafiltrate and the filtered blood to the mammal; and means fordiscarding any portion of the post adsorption ultrafiltrate and anyportion of the filtered blood which is not returned to the mammal.
 24. Ahemofiltration system to treat an inflammatory mediator related diseasesuch as sepsis and septic shock in a mammal comprising: a blood pump topump a blood stream from the mammal; a hemofilter operable to removeultrafiltrate from the blood stream extracted from the mammal and tocreate a filtered blood stream and an ultrafiltrate stream; anadsorptive device containing at least one adsorbent material operable toreceive the ultrafiltrate stream from the hemofilter and to removeinflammatory mediators therefrom to create a post adsorptionultrafiltrate stream; means for selectively combining the postadsorption ultrafiltrate stream with the filtered blood stream alongwith returning the combined stream to the mammal to treat theinflammatory mediator related disease; a first tubing to transfer thecombined stream to the mammal; a second tubing to transfer any of thepost adsorption ultrafiltrate stream which is not returned to the mammalto a waste reservoir; at least a first ultrafiltrate pump operablycoupled with the adsorptive device to assist with transferring the postadsorptive ultrafiltrate stream from the adsorptive device; and at leasta second ultrafiltrate waste pump operably coupled with the secondtubing to assist with transferring any of the post adsorptionultrafiltrate stream which is not returned to the mammal to the wastereservoir.
 25. The system of claim 24 , wherein the adsorbent materialis comprised of resins selected from a group consisting of immobilizedpolymyxin B, polystyrene-derivative fibers, charged exchange resins,neutral exchange resins; polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, andcellulose derivatives, specific antagonist coated materials, andspecific antibody coated materials.
 26. The system of claim 24 , using ahemofilter to remove the ultrafiltrate from the blood stream to createthe filtered blood stream and the ultrafiltrate stream comprising plasmawater, electrolytes blood peptides and proteins.
 27. The system of claim24 , wherein the hemofilter comprises a membrane having at least onepore with a pore size selected to be larger than a molecular size of theblood peptides and proteins.
 28. The system of claim 24 , wherein thehemofilter comprises a membrane and a jacket, wherein the membrane isselected from the group of polysulfone, polyacrylonitrile,polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, andcellulose derivatives, and the jacket comprises polycarbonate.